Potential application of liver organoids in liver disease models and transplantation therapy

doi:10.12307/2025.359

Chinese Journal of Tissue Engineering Research ›› 2025, Vol. 29 ›› Issue (8): 1684-1692.doi: 10.12307/2025.359

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Potential application of liver organoids in liver disease models and transplantation therapy

Yuan Weibo1, 2, 3, Liu Chan1, 2, 3, 4, 5, Yu Limei1, 2, 3, 4, 5

1Guizhou Key Laboratory of Cell Engineering, 3Guizhou Stem Cell Clinical Application and New Drug Research and Development Engineering Research Center, 4Guizhou Biotherapy Talent Base, 5Zunyi Stem Cell and Regenerative Medicine Engineering Research Center, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China; 2Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine Co-Built by Province and Ministry of Education, Zunyi Medical University, Zunyi 563000, Guizhou Province, China

Received:2024-03-13 Accepted:2024-05-17 Online:2025-03-18 Published:2024-07-06
Contact: Yu Limei, MD, Professor, Doctoral supervisor, 1Guizhou Key Laboratory of Cell Engineering, 3Guizhou Stem Cell Clinical Application and New Drug Research and Development Engineering Research Center, 4Guizhou Biotherapy Talent Base, 5Zunyi Stem Cell and Regenerative Medicine Engineering Research Center, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China; 2Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine Co-Built by Province and Ministry of Education, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
About author:Yuan Weibo, Master candidate, 1Guizhou Key Laboratory of Cell Engineering, 3Guizhou Stem Cell Clinical Application and New Drug Research and Development Engineering Research Center, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China; 2Collaborative Innovation Center for Tissue Injury Repair and Regenerative Medicine Co-Built by Province and Ministry of Education, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Supported by:
2023 Regional Science Foundation Project of National Natural Science Foundation of China, No. 82360047 (to YLM)

Abstract

Abstract: BACKGROUND: Liver organoids are of great significance to elucidate the exact pathological mechanism of liver diseases and the treatment of liver diseases.
OBJECTIVE: To summarize the basic research in this field at home and abroad, review the important research progress in the construction of liver organoids, disease modeling and transplantation therapy, and discuss the application prospect of combined tissue engineering technology of liver organoids.
METHODS: The relevant articles included in PubMed and CNKI databases were searched. The English and Chinese search terms were “liver, organoids, liver diseases.” The main search time was from April 2018 to April 2024. Duplicate literature was excluded by manual reading. Finally, 94 articles were included for review and analysis.
RESULTS AND CONCLUSION: The seed cells constructed by liver organoids are mainly concentrated in adult cells and pluripotent stem cells, which promote the generation of organoids by assisting various cytokines to participate in signal guidance and providing 3D microenvironment by extracellular matrix. However, the overall maturity is not high, which is expected to improve this problem by combining tissue engineering technology. In vitro disease modeling is mainly studied in the field of simple diseases and single-gene genetic diseases. Organoids highly retain patient genetic characteristics, and it is expected to simulate more complex liver diseases and clarify deeper pathological mechanisms by combining CRISPR-Cas9 gene correction and other emerging technologies. In vivo transplantation treatment, liver organoids can be safely and effectively implanted, showing amazing liver function replacement potential, tissue regeneration ability, and may also be combined with other tissue engineering materials to achieve therapeutic purposes.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: liver organoids, stem cell, seed cell, liver disease, disease modeling, in vivo transplantation, review

CLC Number:

Yuan Weibo, Liu Chan, Yu Limei. Potential application of liver organoids in liver disease models and transplantation therapy[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(8): 1684-1692.

Figures/Tables 7

一种是从iPSCs生成成熟肝细胞，随后构建肝脏类器官[40-41]。使用富含激活素 A、骨形态发生蛋白2、成纤维生长因子4、肝细胞生长因子、重组人角质细胞生长因子和抑瘤素M的培养基实现2维成熟肝细胞的分化，然后进行三维培养，加入表皮生长因子、转化生长因子α、成纤维生长因子7、成纤维生长因子10、肝细胞生长因子、转化生长因子β抑制剂A83-01、ROCK抑制剂Y-27632、地塞米松和抑瘤素M因子，最终获得肝脏类器官[40]。另一种是先建立iPSCs分化早期的球状体，然后进一步诱导为成熟肝脏类器官[42]。使用富含激活素 A、骨形态发生蛋白4、GSK-3抑制剂 CHIR99021和成纤维生长因子4的培养基生成前肠细胞，再将前肠细胞包埋种植于含有成纤维生长因子2、表皮生长因子、血管内皮生长因子、GSK-3 抑制剂 CHIR99021和转化生长因子β抑制剂A83-01等因子的类器官形成培养基进行三维培养，类器官形成后，切换肝脏成熟培养基培养，最终形成肝脏类器官[42]。虽然大多数方案包括多个阶段，但都是通过激活肝细胞成熟过程中的关键信号通路，进而通过特定的发育标记来验证分化效率[43]。一般来说，通过多个阶段进行更加精确的信号调控诱导细胞分化，可以得到更高的分化效率。总之，肝细胞或干细胞衍生的肝脏类器官具有强大的增殖能力，具有基因组稳定性的优势，且肝脏类器官在一定的微环境下除向肝细胞分化外，还可向胆管细胞分化[32，44]。 2.1.2 肝脏类器官的疾病模型疾病模型对于研究疾病机制和开创治疗方法是必须的，但是由于动物与人类种属和基因组的差异，动物肝脏疾病模型与人类肝脏疾病致病机制存在不同，人类疾病的组织学复杂性和遗传异质性在许多动物模型中没有得到很好的回馈[45]。目前，利用人iPSCs、胚胎干细胞、肝细胞、肝星状细胞和枯否细胞、肝内胆管细胞和肝外胆管细胞、胆囊细胞、良性胆囊腺瘤组织细胞、成人胆管衍生的双能祖细胞、原发性硬化性胆管炎患者的胆管细胞构建的肝脏类器官已应用于多种肝脏疾病的建模及致病机制研究，见表1。 2.2 肝脏类器官的体内移植肝脏类器官的终极目标是创造出可移植的肝脏组织替代受损肝脏组织，快速地恢复肝功能[60]。富马酰乙酸水解酶缺乏会导致肝功能衰竭，HUCH等[61]培养的Lgr5+细胞衍生的肝脏类器官具有成熟肝细胞的特征与功能，移植到富马酰乙酸水解酶缺乏小鼠中，肝衰竭小鼠存活率显著增加，并在肝组织中观察到主要由肝细胞核因子4α和角蛋白19阳性的成熟肝细胞组成的富马酰乙酸水解酶阳性结节。同年，TAKEBE课题组[18]将iPSCs生成内胚层细胞通过内皮细胞和间充质干细胞之间的相互作用建立的肝脏类器官移植到肠系膜上探索类器官的功能性和相容性，肝脏类器官移植48 h内与宿主血管系统建立了联系，并执行白蛋白产生和药物代谢功能，成功挽救更昔氯韦诱导的药物性急性肝衰竭，这些是科学家最早探索肝脏类器官体内移植成功治疗肝脏疾病的实验，随后肝脏类器官的体内移植应用得到更多肝脏疾病模型的验证，见表2。此外，采用含有猪肝细胞与人脐静脉内皮细胞球体的改良生物人工肝治疗猴的急性肝衰竭，明显提高了动物的生存率，降低了血氨和炎症因子水平，改善了受损肝脏的再生微环境，很好地恢复了衰竭动物的肝脏功能[62]。"

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Potential application of liver organoids in liver disease models and transplantation therapy

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